Phytomedicine. 2024 Aug 22;134:155971. doi: 10.1016/j.phymed.2024.155971. Online ahead of print.

ABSTRACT

BACKGROUND: Punica granatum L., commonly known as pomegranate, is renowned for its health benefits, primarily associated with the consumption of its fruit and seeds. However, its non-edible parts, including leaves, have been used in traditional medicine as a remedy with anti-inflammatory and anti-diabetic properties. Considering the abundance of bioactive compounds, predominantly flavonols, flavones, and tannins P. granatum leaf (PGL) extract holds potential as health-promoting agent. Yet, its effect on longevity and healthspan remains largely unexplored.

PURPOSE: Our study aims to explore the potential of PGL extract to enhance healthspan and ameliorate age-related frailty in Caenorhabditis elegans. Additionally, we seek to elucidate its effect on the molecular signaling networks associated with stress resistance and longevity.

METHODS: After characterizing the extract metabolite profile by NMR spectroscopy, phenotypic and stress analyses were performed. In order to establish the molecular mechanism of action, the involvement of signaling pathways key to longevity were investigated by means of real-time quantitative PCR (RT-qPCR) and the use of transgenic strains (MIR13, MAH240, LD1, and OH16024). In addition, the effect of PGL on metabolism and lipid accumulation, as well as mitochondrial homeostasis, was examined.

RESULTS: The PGL extract supplementation significantly enhanced stress resistance and extended the lifespan of C. elegans. Additionally, it improved locomotion, as well as metabolic and mitochondrial functions, indicating an overall improvement in health. The molecular mechanisms highlight the coordinated regulation of stress response, metabolic homeostasis, and longevity signaling pathways. Specifically, our results demonstrate the essential roles of HLH-30/TFEB, in conjunction with DAF-16/FOXO and SKN-1/NRF2, as mediators of the PGL extract effect on healthspan.

CONCLUSION: Our findings emphasize the potential of PGL extract to ameliorate age-related decline, induce longevity and further enhance healthspan. Given the diverse effects on the molecular network associated with stress-adaptations, longevity and metabolic control, PGL extract might become a promising natural product with a particular importance to the field of gerontology.

PMID:39197398 | DOI:10.1016/j.phymed.2024.155971

Curr Opin Biotechnol. 2024 Aug 27;89:103183. doi: 10.1016/j.copbio.2024.103183. Online ahead of print.

ABSTRACT

The impact of bacteria and viruses on tumor growth has long been recognized. In recent decades, interest in the role of microorganisms in the tumor microenvironment (TME) has expanded. Infections induce metabolic reprogramming and influence immune responses within the TME that may either support proliferation and metastasis or limit tumor growth. The natural ability to infect cells and alter the TME is also utilized for cancer detection and treatment. In this review, we discuss recent discoveries about the mechanisms of bacteria and viruses affecting TME, as well as strategies in cancer therapy focusing on metabolic alterations. Infections with engineered bacteria and viruses represent promising therapeutic approaches to develop novel and more effective therapies to constrain tumor growth.

PMID:39197341 | DOI:10.1016/j.copbio.2024.103183

Database (Oxford). 2024 Aug 28;2024:baae084. doi: 10.1093/database/baae084.

ABSTRACT

The Australian Biosecurity Genomic Database (ABGD) is a curated collection of reference viral genome sequences based on the Australian National Notifiable Disease List of Terrestrial Animals. It was created to facilitate the screening of high-throughput sequencing (HTS) data for the potential presence of viruses associated with notifiable disease. The database includes a single verified sequence (the exemplar species sequence, where relevant) for each of the 60 virus species across 21 viral families that are associated with or cause these notifiable diseases, as recognized by the World Organisation for Animal Health. The open-source ABGD on GitHub provides usage guidance documents and is intended to support building a culture in Australian HTS communities that promotes the use of quality-assured, standardized, and verified databases for Australia's national biosecurity interests. Future expansion of the database will include the addition of more strains or subtypes for highly variable viruses, viruses causing diseases of aquatic animals, and genomes of other types of pathogens associated with notifiable diseases, such as bacteria. Database URL: https://github.com/ausbiopathgenDB/AustralianBiosecurityGenomicDatabase.

PMID:39197058 | DOI:10.1093/database/baae084

Sci Adv. 2024 Aug 30;10(35):eadq3942. doi: 10.1126/sciadv.adq3942. Epub 2024 Aug 28.

ABSTRACT

Strigolactones exhibit dual functionality as regulators of plant architecture and signaling molecules in the rhizosphere. The important model crop rice exudes a blend of different strigolactones from its roots. Here, we identify the inaugural noncanonical strigolactone, 4-oxo-methyl carlactonoate (4-oxo-MeCLA), in rice root exudate. Comprehensive, cross-species coexpression analysis allowed us to identify a cytochrome P450, OsCYP706C2, and two methyl transferases as candidate enzymes for this noncanonical rice strigolactone biosynthetic pathway. Heterologous expression in yeast and Nicotiana benthamiana indeed demonstrated the role of these enzymes in the biosynthesis of 4-oxo-MeCLA, which, expectedly, is derived from carlactone as substrate. The oscyp706c2 mutants do not exhibit a tillering phenotype but do have delayed mycorrhizal colonization and altered root phenotype. This work sheds light onto the intricate complexity of strigolactone biosynthesis in rice and delineates its role in symbiosis and development.

PMID:39196928 | DOI:10.1126/sciadv.adq3942

Sci Adv. 2024 Aug 30;10(35):eado3232. doi: 10.1126/sciadv.ado3232. Epub 2024 Aug 28.

ABSTRACT

Irreversibility, in which a transient perturbation leaves a system in a new state, is an emergent property in systems of interacting entities. This property has well-established implications in statistical physics but remains underexplored in biological networks, especially for bacteria and other prokaryotes whose regulation of gene expression occurs predominantly at the transcriptional level. Focusing on the reconstructed regulatory network of Escherichia coli, we examine network responses to transient single-gene perturbations. We predict irreversibility in numerous cases and find that the incidence of irreversibility increases with the proximity of the perturbed gene to positive circuits in the network. Comparison with experimental data suggests a connection between the predicted irreversibility to transient perturbations and the evolutionary response to permanent perturbations.

PMID:39196926 | DOI:10.1126/sciadv.ado3232

J Physiol. 2024 Aug 28. doi: 10.1113/JP286559. Online ahead of print.

ABSTRACT

Epithelial Na+ channels (ENaCs) are activated by proteolysis of the α and γ subunits at specific sites flanking embedded inhibitory tracts. To examine the role of α subunit proteolysis in channel activation in vivo, we generated mice lacking the distal furin cleavage site in the α subunit (αF2M mice). On a normal Na+ control diet, no differences in ENaC protein abundance in kidney or distal colon were noted between wild-type (WT) and αF2M mice. Patch-clamp analyses revealed similar levels of ENaC activity in kidney tubules, while no physiologically relevant differences in blood chemistry or aldosterone levels were detected. Male αF2M mice did exhibit diminished ENaC activity in the distal colon, as measured by amiloride-sensitive short-circuit current (ISC). Following dietary Na+ restriction, WT and αF2M mice had similar natriuretic and colonic ISC responses to amiloride. However, single-channel activity was significantly lower in kidney tubules from Na+-restricted αF2M mice compared with WT littermates. ENaC α and γ subunit expression in kidney and distal colon were also enhanced in Na+-restricted αF2M vs. WT mice, in association with higher aldosterone levels. These data provide evidence that disrupting α subunit proteolysis impairs ENaC activity in vivo, requiring compensation in response to Na+ restriction. KEY POINTS: The epithelial Na+ channel (ENaC) is activated by proteolytic cleavage in vitro, but key questions regarding the role of ENaC proteolysis in terms of whole-animal physiology remain to be addressed. We studied the in vivo importance of this mechanism by generating a mouse model with a genetic disruption to a key cleavage site in the ENaC's α subunit (αF2M mice). We found that αF2M mice did not exhibit a physiologically relevant phenotype under normal dietary conditions, but have impaired ENaC activation (channel open probability) in the kidney during salt restriction. ENaC function at the organ level was preserved in salt-restricted αF2M mice, but this was associated with higher aldosterone levels and increased expression of ENaC subunits, suggesting compensation was required to maintain homeostasis. These results provide the first evidence that ENaC α subunit proteolysis is a key regulator of channel activity in vivo.

PMID:39196791 | DOI:10.1113/JP286559

Int J Syst Evol Microbiol. 2024 Aug;74(8). doi: 10.1099/ijsem.0.006500.

ABSTRACT

Two new strains JP48T and JP55 affiliated with the acidobacterial class Terriglobia have been isolated from fen soil sampled in the Fichtelgebirge Mountains near Bayreuth, Germany. Both strains were Gram-stain-negative, non-motile, non-spore-forming rods that divide by binary fission, segregate exopolysaccharide-like material and form capsules. Strains JP48T and JP55 grew at 4-36 °C (optimum at 27 °C), pH 3.6-7.3 (optimum at pH 4.6-5.5) and with NaCl concentrations of 0-3% (optimum at 1.0%; w/v). Strains JP48T and JP55 grew aerobically on a wide range of organic substrates including mono- and oligosaccharides, amino acids and short-chained fatty acids. MK-8 was identified as the major respiratory quinone. The major fatty acids for strains JP48T and JP55 were iso-C15 : 0, C16 : 1 ω7c, C16 : 0 and iso-diabolic acid. Phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, lysophophatidylethanolamine, phosphatidylcholine, unidentified glyco- and glycophospholipids, and unidentified high mass lipid species were the major polar membrane lipids. The G+C content of strains JP48T and JP55 was 57.4 and 57.2 mol%, respectively. The genomes of strains JP48T and JP55 contained nine potential secondary metabolite regions encoding for the compound classes NRPS(-like), T3PKS, terpene, or lanthipeptide class IV. Phylogenetic reconstruction and 16S rRNA gene sequence similarities of 98.3 and 96.9% identified Edaphobacter dinghuensis DHF9T and Edaphobacter lichenicola DSM 104462T as the most closely related type strains to strains JP48T and JP55. Based on their phenotype, phylogeny and chemotaxonomy, we propose the novel species Edaphobacter paludis sp. nov. (type strain JP48T=DSM 109919T=CECT 30269T; additional strain JP55=DSM 109920=CECT 30268) within the class Terriglobia of the phylum Acidobacteriota.

PMID:39196616 | DOI:10.1099/ijsem.0.006500

Elife. 2024 Aug 28;12:RP93562. doi: 10.7554/eLife.93562.

ABSTRACT

The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical significance. However, there are dozens of unique atomic-resolution structures of these aggregates, and such a highly polymorphic nature of the α-synuclein fibrils hampers efforts in disease-relevant in vitro studies on α-synuclein amyloid aggregation. In order to better understand the factors that affect polymorph selection, we studied the structures of α-synuclein fibrils in vitro as a function of pH and buffer using cryo-EM helical reconstruction. We find that in the physiological range of pH 5.8-7.4, a pH-dependent selection between Type 1, 2, and 3 polymorphs occurs. Our results indicate that even in the presence of seeds, the polymorph selection during aggregation is highly dependent on the buffer conditions, attributed to the non-polymorph-specific nature of secondary nucleation. We also uncovered two new polymorphs that occur at pH 7.0 in phosphate-buffered saline. The first is a monofilament Type 1 fibril that highly resembles the structure of the juvenile-onset synucleinopathy polymorph found in patient-derived material. The second is a new Type 5 polymorph that resembles a polymorph that has been recently reported in a study that used diseased tissues to seed aggregation. Taken together, our results highlight the shallow amyloid energy hypersurface that can be altered by subtle changes in the environment, including the pH which is shown to play a major role in polymorph selection and in many cases appears to be the determining factor in seeded aggregation. The results also suggest the possibility of producing disease-relevant structure in vitro.

PMID:39196271 | DOI:10.7554/eLife.93562

Nat Cardiovasc Res. 2022 Jan;1(1):4-5. doi: 10.1038/s44161-021-00008-2.

NO ABSTRACT

PMID:39196109 | DOI:10.1038/s44161-021-00008-2

Nat Cardiovasc Res. 2022 Sep;1(9):794-795. doi: 10.1038/s44161-022-00129-2.

NO ABSTRACT

PMID:39196081 | DOI:10.1038/s44161-022-00129-2

Nat Cardiovasc Res. 2024 Aug;3(8):987-1002. doi: 10.1038/s44161-024-00512-1. Epub 2024 Jul 18.

ABSTRACT

Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific and saturable binding of cTnI to F1FO-ATP synthase was demonstrated in vitro using immune-captured ATP synthase and in cells using proximity ligation assay. cTnI binding doubled ATPase activity, whereas skeletal troponin I and several human pathogenic cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally designed peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro and reduced cardiac injury following transient ischemia in vivo. We suggest that cTnI-bound ATP synthase results in lower ATP levels, and releasing this interaction during cardiac ischemia-reperfusion may increase the reservoir of functional mitochondria to reduce cardiac injury.

PMID:39196031 | DOI:10.1038/s44161-024-00512-1

Nat Cardiovasc Res. 2022 Nov;1(11):978-979. doi: 10.1038/s44161-022-00161-2.

NO ABSTRACT

PMID:39195916 | DOI:10.1038/s44161-022-00161-2

Nat Cardiovasc Res. 2023 Jun;2(6):500-501. doi: 10.1038/s44161-023-00286-y.

NO ABSTRACT

PMID:39195886 | DOI:10.1038/s44161-023-00286-y

Toxins (Basel). 2024 Aug 20;16(8):367. doi: 10.3390/toxins16080367.

ABSTRACT

The climate-change-coupled fungal burden in crop management and the need to reduce chemical pesticide usage highlight the importance of finding sustainable ways to control Aspergillus flavus. This study examines the effectiveness of 50 Pseudomonas isolates obtained from corn rhizospheres against A. flavus in both solid and liquid co-cultures. The presence and quantity of aflatoxin B1 (AFB1) and AFB1-related compounds were determined using high-performance liquid chromatography-high resolution mass spectrometry analysis. Various enzymatic- or non-enzymatic mechanisms are proposed to interpret the decrease in AFB1 production, accompanied by the accumulation of biosynthetic intermediates (11-hydroxy-O-methylsterigmatocystin, aspertoxin, 11-hydroxyaspertoxin) or degradation products (the compounds C16H10O6, C16H14O5, C18H16O7, and C19H16O8). Our finding implies the upregulation or enhanced activity of fungal oxidoreductases and laccases in response to bacterial bioactive compound(s). Furthermore, non-enzymatic reactions resulted in the formation of additional degradation products due to acid accumulation in the fermented broth. Three isolates completely inhibited AFB1 or any AFB1-related compounds without significantly affecting fungal growth. These bacterial isolates supposedly block the entire pathway for AFB1 production in the fungus during interaction. Apart from identifying effective Pseudomonas isolates as potential biocontrol agents, this work lays the foundation for exploring new bacterial bioactive compounds.

PMID:39195777 | DOI:10.3390/toxins16080367

Toxins (Basel). 2024 Jul 27;16(8):333. doi: 10.3390/toxins16080333.

ABSTRACT

Cyanobacteria are adaptable and dominant organisms that exist in many harsh and extreme environments due to their great ecological tolerance. They produce various secondary metabolites, including cyanotoxins. While cyanobacteria are well studied in surface waters and some aerial habitats, numerous other habitats and niches remain underexplored. We collected 61 samples of: (i) biofilms from springs, (ii) aerial microbial mats from buildings and subaerial mats from caves, and (iii) water from borehole wells, caves, alkaline, saline, sulphidic, thermal, and iron springs, rivers, seas, and melted cave ice from five countries (Croatia, Georgia, Italy, Serbia, and Slovenia). We used (q)PCR to detect cyanobacteria (phycocyanin intergenic spacer-PC-IGS and cyanobacteria-specific 16S rRNA gene) and cyanotoxin genes (microcystins-mcyE, saxitoxins-sxtA, cylindrospermopsins-cyrJ), as well as amplicon sequencing and morphological observations for taxonomic identification. Cyanobacteria were detected in samples from caves, a saline spring, and an alkaline spring. While mcyE or sxtA genes were not observed in any sample, cyrJ results showed the presence of a potential cylindrospermopsin producer in a biofilm from a sulphidic spring in Slovenia. This study contributes to our understanding of cyanobacteria occurrence in diverse habitats, including rare and extreme ones, and provides relevant methodological considerations for future research in such environments.

PMID:39195743 | DOI:10.3390/toxins16080333

Mar Drugs. 2024 Jul 23;22(8):329. doi: 10.3390/md22080329.

ABSTRACT

Carotenoids, with their diverse biological activities and potential pharmaceutical applications, have garnered significant attention as essential nutraceuticals. Microalgae, as natural producers of these bioactive compounds, offer a promising avenue for sustainable and cost-effective carotenoid production. Despite the ability to cultivate microalgae for its high-value carotenoids with health benefits, only astaxanthin and β-carotene are produced on a commercial scale by Haematococcus pluvialis and Dunaliella salina, respectively. This review explores recent advancements in genetic engineering and cultivation strategies to enhance the production of lutein by microalgae. Techniques such as random mutagenesis, genetic engineering, including CRISPR technology and multi-omics approaches, are discussed in detail for their impact on improving lutein production. Innovative cultivation strategies are compared, highlighting their advantages and challenges. The paper concludes by identifying future research directions, challenges, and proposing strategies for the continued advancement of cost-effective and genetically engineered microalgal carotenoids for pharmaceutical applications.

PMID:39195445 | DOI:10.3390/md22080329

Cells. 2024 Aug 13;13(16):1339. doi: 10.3390/cells13161339.

ABSTRACT

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) constitute an appealing tool for drug discovery, disease modeling, and cardiotoxicity screening. However, their physiological immaturity, resembling CMs in the late fetal stage, limits their utility. Herein, we have developed a novel, scalable cell culture medium designed to enhance the maturation of hPSC-CMs. This medium facilitates a metabolic shift towards fatty acid utilization and augments mitochondrial function by targeting Acetyl-CoA carboxylase 2 (ACC2) with a specific small molecule inhibitor. Our findings demonstrate that this maturation protocol significantly advances the metabolic, structural, molecular and functional maturity of hPSC-CMs at various stages of differentiation. Furthermore, it enables the creation of cardiac microtissues with superior structural integrity and contractile properties. Notably, hPSC-CMs cultured in this optimized maturation medium display increased accuracy in modeling a hypertrophic cardiac phenotype following acute endothelin-1 induction and show a strong correlation between in vitro and in vivo target engagement in drug screening efforts. This approach holds promise for improving the utility and translatability of hPSC-CMs in cardiac disease modeling and drug discovery.

PMID:39195229 | DOI:10.3390/cells13161339

Biology (Basel). 2024 Aug 10;13(8):606. doi: 10.3390/biology13080606.

ABSTRACT

Cellular molecules interact with one another in a structured manner, defining a regulatory network topology that describes cellular mechanisms. Genetic mutations alter these networks' pathways, generating complex disorders such as autism spectrum disorder (ASD). Boolean models have assisted in understanding biological system dynamics since Kauffman's 1969 discovery, and various analytical tools for regulatory networks have been developed. This study examined the protein-protein interaction network created in our previous publication of four ASD patients using the SPIDDOR R package, a Boolean model-based method. The aim is to examine how patients' genetic variations in INTS6L, USP9X, RSK4, FGF5, FLNA, SUMF1, and IDS affect mTOR and Wnt cell signaling convergence. The Boolean network analysis revealed abnormal activation levels of essential proteins such as β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD. These proteins affect gene expression, translation, cell adhesion, shape, and migration. Patients 1 and 2 showed consistent patterns of increased β-catenin activity and decreased MTORC1, RPS6, and eIF4E activity. However, patient 2 had an independent decrease in Cadherin and SMAD activity due to the FLNA mutation. Patients 3 and 4 have an abnormal activation of the mTOR pathway, which includes the MTORC1, RPS6, and eIF4E genes. The shared mTOR pathway behavior in these patients is explained by a shared mutation in two closely related proteins (SUMF1 and IDS). Diverse activities in β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD contributed to the reported phenotype in these individuals. Furthermore, it unveiled the potential therapeutic options that could be suggested to these individuals.

PMID:39194544 | DOI:10.3390/biology13080606

Biology (Basel). 2024 Jul 26;13(8):564. doi: 10.3390/biology13080564.

ABSTRACT

Breast cancer heterogeneity presents a significant challenge in clinical therapy, such as over-treatment and drug resistance. These challenges are largely due to its obscure normal epithelial origins, evolutionary stability, and transitions on the cancer subtypes. This study aims to elucidate the cellular emergence and maintenance of heterogeneous breast cancer via quantitative bio-process modeling, with potential benefit to therapeutic strategies for the disease. An endogenous molecular-cellular hypothesis posits that both pathological and physiological states are phenotypes evolved from and shaped by interactions among a number of conserved modules and cellular factors within a biological network. We hereby developed a model of core endogenous network for breast cancer in accordance with the theory, quantifying its intrinsic dynamic properties with dynamic modeling. The model spontaneously generates cell states that align with molecular classifications at both the molecular and modular level, replicating four widely recognized molecular subtypes of the cancer and validating against data extracted from the TCGA database. Further analysis shows that topologically, a singular progression gateway from normal breast cells to cancerous states is identified as the Luminal A-type breast cancer. Activated positive feedback loops are found to stabilize cellular states, while negative feedback loops facilitate state transitions. Overall, more routes are revealed on the cellular transition between stable states, and a traceable count explains the origin of breast cancer heterogeneity. Ultimately, the research intended to strength the search for therapeutic targets.

PMID:39194502 | DOI:10.3390/biology13080564

ACS Meas Sci Au. 2024 Jun 4;4(4):338-417. doi: 10.1021/acsmeasuresciau.3c00068. eCollection 2024 Aug 21.

ABSTRACT

Proteomics is the large scale study of protein structure and function from biological systems through protein identification and quantification. "Shotgun proteomics" or "bottom-up proteomics" is the prevailing strategy, in which proteins are hydrolyzed into peptides that are analyzed by mass spectrometry. Proteomics studies can be applied to diverse studies ranging from simple protein identification to studies of proteoforms, protein-protein interactions, protein structural alterations, absolute and relative protein quantification, post-translational modifications, and protein stability. To enable this range of different experiments, there are diverse strategies for proteome analysis. The nuances of how proteomic workflows differ may be challenging to understand for new practitioners. Here, we provide a comprehensive overview of different proteomics methods. We cover from biochemistry basics and protein extraction to biological interpretation and orthogonal validation. We expect this Review will serve as a handbook for researchers who are new to the field of bottom-up proteomics.

PMID:39193565 | PMC:PMC11348894 | DOI:10.1021/acsmeasuresciau.3c00068